1. Novel Anticoagulants (NOACs) in Non Valvular Atrial Fibrillation
Raj Chakka, M.D.
Electrophysiologist
CHI St. Vincent Heart Clinic Arkansas
April 25, 2015

2. CHADS VASc

3. Warfarin
 Warfarin is an extremely effective drug for stroke prevention in AF patients, reducing stroke by 68% and mortality by 26%.
60% of patients never get warfarin, around half of patients who do get it stop taking it, and of those who still take it only half are in therapeutic range. So only a small minority are well treated.

4. Warfarin Target INR 2-3 Absolute risk reduction with warfarin
31 ischemic strokes prevented each year per patients treated
Warfarin superior to Aspirin alone
Antiplatelet agents like Clopidogrel + Aspirin increased major bleeding and no net benefit over Aspirin alone
TTR < 58% showed no benefit of warfarin over combination antiplatelet therapy.

5. NOACs
superior or similar stroke rates to warfarin, with reduced intracranial hemorrhage
Ease of use and no INR testing needed
 "alternatives to warfarin," while Canadian guidelines and those by the ACCP have made the jump to the new agents being "preferred to warfarin."

6. Tials of NOACs Indication Dabigatran Rivoraxaban Apixaban Edoxaban
Non valvular atrial fibrillation
RE-LY
Re-LYABLE
ROCKET-AF
AVERROES
ARISTOTLE
ENGAGE-AF
ACS
REDEEM
(Phase II)
ATLAS
ACS 2-TIMI 51
APPRAISE-2
Discontinued due to increased bleeding
THR, TKR,
VTE
Acute medical illness

7. Advantages of NOACs over Warfarin
Real World Implications
Rapid onset of action
No need for bridging with IV Heparin etc
Predictable anticoagulant effect
No need to routinely monitor INR etc
Specific coagulation enzyme target
Low risk of off-target adverse effects
Low food interactions
Can eat greens/salads etc
Lower risk of drug interactions
Few restrictions in use of other drugs
Lower adverse events
Skin necrosis in protein C or S deficiency
Risk of osteoporosis

8. Downside of NOACs
Very short half-lives, which will be hazardous if patients are noncompliant.
Lack of effect assay (we do not know if someone is compliant or not)
Renal function needs to be monitored.
No reversal agents at this time

9. 4 NOACs Characteristic Dabigatran (Pradaxatm) Rivaroxaban (Xareltotm)
Apixaban
(Eliquistm)
Edoxaban
Target
Thrombin
Factor Xa
Half-life (hours)
12-14
7-13
8-13
9-11
Renal Clearance
80%
66%
~25%
35%
Dosing
150 mg BID
20 mg QD
5 mg PO BID
Fixed, QD
Drug interactions
Rifampin,
Quinidine,
Amiodarone,
P-gp inhibitors
Potent CYP3A4 and
Potent CYP3A4 inhibitors
CYP involvement NO
CYP3A4 (15%)
CYP3A4 (32%)
CYP3A4

10. Rivoraxaban vs Warfarin
Risk-Benefit balance in ROCKET – AF 1000 patient treated with Rivoraxaban instead of Warfarin
Rivoraxaban vs Warfarin
Benefit
3 fewer hemorrhagic strokes
4 fewer ischemic strokes
No monitoring/fixed dose
Limited potential for drug and food interactions
Risk
7 excessive bleeding
3 excess blood transfusions
5 excess hemoglobin drop > 2 g/dl
6 excess SAEs leadsing to Rx discontinuation
Increased cost
No antidote

11. Clinical Tid Bits!
Some people prefer a once-daily dosage (ie, Rivaroxaban, Adoxaban).
Dabigatran should be avoided in severe renal failure. Renal function is not so much of a problem with Rivaroxaban but it still needs to be considered. Apixaban least renally cleared and preferred. Avoid Adoxaban if craetinine clearance > 95 ml/min
Only the low dose of Dabigatran should be used with the P-glycoprotein (Pgp) inhibitor Verapamil, and close clinical surveillance is recommended especially in patients with renal impairment with Quinidine and Amiodarone.
Dabigatran dose should be decreased to 75 mg BID with Dronedarone or systemic Ketoconazole in patients with moderate renal impairment (CrCl ml/min).
Dabigatran can be dialysed out of the system; Rivaroxaban cannot.
For ACS patients, there is better data for Rivaroxaban (in low dose) from the ATLAS trial.
There is concern over the higher dose of Dabigatran in the elderly.

12. Crcl < 15 do not use Dabigatran or Rivaroxaban
Take Dabigatran with a full glass of water to reduce dyspepsia and GI side effects
Apixaban is the only NOACs that can be used in ESRD and in those on hemodialysis
Adjust dose of Apixaban based on age, weight, creatinine
Decrease dose to 2.5 mg BID if ≥ 2 of the criteria – age ≥ 80, Weight ≤ 60 Kg, or serum creatinine ≥ 1.5 mg/dL
Boxed warning on Rivaroxaban – premature discontinuation increases the risk of thromboembolic events.
Keep all these medications in original bottles delivered by pharmacy

13. How do we decrease risk clinically?
Treat BP well
Avoid constipation in anticoagulation patients
Be wary of using NOACs with dual anti platelet agents (eg: Aspirin + Plavix)

14. Management of bleeding* * based on non clinical data and volunteers
Moderate to severe bleeding
Life threatening bleeding
Symptomatic treatment
Mechanical compression
Surgical intervention
Fluid replacement
Hemodynamic support
Blood product treatment
Hemodialysis (60%, < 2-3 hrs)
Oral Charcoal (<2hrs)
rFVIIa
PCC
Prohemostatic agents
Aprotinin, ECSA
Tranexaine acid
Desmopressin
Charcoal filtration
aDabi-Fab, PRT 4445
Andexanet-Alfa (Annexa-R) – being studied as a reversal agent in Phase III trials

15. 40% of patients who have indication for anticoagulation still do not receive anticoagulation
Comparison with left atrial occlusion devices – NOACs superior in early data

16. What CHADS/CHADS-VASc don’t account for
Echo parameters (LA size, LVH)
Renal/Hepatic
Pattern of AF
Bleeding Risk

17. HAS-BLED